دورية أكاديمية
أعرض في EDS

Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.

التفاصيل البيبلوغرافية
العنوان: Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.
المؤلفون: Negraes PD; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Trujillo CA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. clebertrujillo@gmail.com., Yu NK; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA., Wu W; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Yao H; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Liang N; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Lautz JD; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.; Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA., Kwok E; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., McClatchy D; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA., Diedrich J; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA., de Bartolome SM; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA., Truong J; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Szeto R; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Tran T; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA., Herai RH; Experimental Multiuser Laboratory, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Paraná, Brazil., Smith SEP; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.; Graduate Program in Neuroscience, University of Washington, Seattle, WA, USA., Haddad GG; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA., Yates JR 3rd; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA., Muotri AR; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. muotri@ucsd.edu.; Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA, USA. muotri@ucsd.edu.; Center for Academic Research and Training in Anthropogeny (CARTA), La Jolla, CA, USA. muotri@ucsd.edu.
المصدر: Molecular psychiatry [Mol Psychiatry] 2021 Nov; Vol. 26 (11), pp. 7047-7068. Date of Electronic Publication: 2021 Apr 22.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE
أسماء مطبوعة: Publication: 2000- : Houndmills, Basingstoke, UK : Nature Publishing Group Specialist Journals
Original Publication: Houndmills, Hampshire, UK ; New York, NY : Stockton Press, c1996-
مواضيع طبية MeSH: Epileptic Syndromes*/genetics, Animals ; Humans ; Mice ; Neurons/metabolism ; Protein Serine-Threonine Kinases ; Proteomics
مستخلص: Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.
(© 2021. The Author(s).)
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معلومات مُعتمدة: R01 MH121487 United States MH NIMH NIH HHS; R00 MH102244 United States MH NIMH NIH HHS; R01 MH113545 United States MH NIMH NIH HHS; K01 AA026911 United States AA NIAAA NIH HHS; R01 MH100175 United States MH NIMH NIH HHS
المشرفين على المادة: EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.22 (CDKL5 protein, mouse)
تواريخ الأحداث: Date Created: 20210423 Date Completed: 20220314 Latest Revision: 20240405
رمز التحديث: 20240405
مُعرف محوري في PubMed: PMC8531162
DOI: 10.1038/s41380-021-01104-2
PMID: 33888873
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5578
DOI:10.1038/s41380-021-01104-2